US5854282A - 3-benzoyl benzofuran derivatives as thyroid hormone antagonists - Google Patents

3-benzoyl benzofuran derivatives as thyroid hormone antagonists Download PDF

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US5854282A
US5854282A US08/776,924 US77692497A US5854282A US 5854282 A US5854282 A US 5854282A US 77692497 A US77692497 A US 77692497A US 5854282 A US5854282 A US 5854282A
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carboxymethoxybenzoyl
diiodo
benzofuran
butyl
isopropyl
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Charlotta Mellin
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Karo Pharma AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to organic compounds which function as nuclear receptor ligands and particularly as thyroid hormone antagonists.
  • Thyroid hormones have various effects on metabolism and oxygen consumption and in particular affect the heart. Thyroid hormones bind to nuclear thyroid hormone receptors. The complex formed by the thyroid hormone and the nuclear receptor binds to particular DNA patterns, termed "thyroid responsive elements” (TRE) in the promoter region of 3,5,3'-triiodothyronine (T-3)-regulated genes. The genes may be positively or negatively regulated.
  • thyroid responsive elements TRE
  • R 1 C 1-4 alkyl
  • R 2 --NHSO 2 R 3 ; NHCOR 3 ; or --NHCONHR 3
  • R 3 --CF 3 ,C 1-3 alkyl, 4-R 4 C 6 H 4 --;
  • R 4 C 1-4 alkoxy-; hydroxy-; fluoro-; or nitro-;
  • the compound may be selected from 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran; 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-isopropylamidobenzofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran; 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)-5-trifluoromethylsulphonamidobenzofuran; 2-isopropyl-3-(3,5
  • the compound is preferably 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran; or 2-n-Butyl-3-(3 ,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido) benzofuran.
  • the compounds of the present invention have an equal or better receptor binding affinity than the thyroid hormone antagonist compounds known in the prior art.
  • the compounds of the present invention have not been described in the literature.
  • the compounds of the present invention may be used in the treatment of disorders which are dependent on the expression of T-3-regulated genes for example, heart arrhythymia, heart failure and hyperthyroidism.
  • a pharmaceutical composition comprising an effective amount of a compound according to the present invention or a pharmaceutically effective salt thereof together with, if necessary, a suitable carrier.
  • a method of treating a patient with a T-3-regulated gene disorder comprising administering a compound according to the present invention or a pharmaceutically acceptable salt thereof, if necessary, in a suitable carrier, to the patient.
  • the disorder may be for example, heart arrhythmia, heart failure, or hyperthyroidism.
  • FIGS. 1-47 in which:
  • FIG. 1 is a T3 dose response curve in TRAP ⁇ cells
  • FIG. 2 illustrates the effects of 2-n-Butyl-3(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran on TRAF ⁇ cells;
  • FIG. 3 illustrates the effects of 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-isopropylamidobenzofuran on TRAF ⁇ cells;
  • FIG. 4 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 5 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 6 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)-5-trifluoromethylsulphonamidobenzofuran on TRAF ⁇ cells;
  • FIG. 7 illustrates the effects of 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran on TRAF ⁇ cells;
  • FIG. 8 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 9 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 10 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-fluorobenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 11 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-nitrobenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 12 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxyphenylureido)benzofuran on TRAF ⁇ cells;
  • FIG. 13 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxyphenylureido)benzofuran on TRAF ⁇ cells;
  • FIG. 14 illustrates the effects of 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 15 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 16 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 17 is a T3 dose response curve in TRAF ⁇ cells
  • FIG. 18 illustrates the effects of 2-n-Butyl-3(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran in TRAF ⁇ cells;
  • FIG. 19 illustrates the effects of 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-isopropylamidobenzofuran on TRAF ⁇ cells;
  • FIG. 20 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 21 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 22 illustrates the effects of 2-Isopropyl-3-(3, 5-diiodo-4-carboxymethoxybenzyl)-5-trifluoromethylsulphonamidobenzofuran on TRAF ⁇ cells;
  • FIG. 23 illustrates the effects of 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran on TRAF ⁇ cells;
  • FIG. 24 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 25 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 26 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-fluorobenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 27 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-nitrobenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 28 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxyphenylureido)benzofuran on TRAF ⁇ cells;
  • FIG. 29 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxyphenylureido)benzofuran on TRAF ⁇ cells;
  • FIG. 30 illustrates the effects of 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 31 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 32 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran on TRAF ⁇ cells;
  • FIG. 33 illustrates competition between 2-n-Butyl-3(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran cpd and 125 -T 3 for binding to ThR ⁇ 1;
  • FIG. 34 illustrates competition between 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-isopropylamidobenzofuran cpd and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 35 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran cpd and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 36 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran and labelled hormones for binding to nuclear receptors;
  • FIG. 37 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxy benzoyl)-5-(4-hydroxybenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 38 illustrates the competition between 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 39 illustrates the competition between 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 40 illustrates competition between 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 41 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-fluorobenzamido)benzofuran and labelled hormones for binding to nuclear receptors;
  • FIG. 42 illustrates competition between 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-nitrobenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 43 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxyphenylureido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 44 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxyphenylureido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 45 illustrates competition between 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 46 illustrates competition between 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran and 125 I-T 3 for binding to ThR ⁇ 1;
  • FIG. 47 illustrates competition between 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran and labelled hormones for binding to nuclear receptors.
  • Triethylamine (15 ml) was added and the solution was refluxed for 3 h.
  • the precipitated triphenylphosphine oxide was removed by filtration and washed with ethylacetate.
  • the filtrate was concentrated and purified by column chromatography on silica with petroleum ether as eluant. 15 g of pure 2-n-butyl-5 nitrobenzofuran was obtained.
  • Tin (IV) chloride (13.4 g, 51.3 mmol) was added dropwise to a solution of the above benzofuran (10 g, 45.6 mol) and anisoyl chloride (10 g, 58.6 mmol) in methylene chloride (100 ml) . The resulting mixture was stirred at room temperature overnight. 2M hydrochloric acid was added and the organic layer was washed with brine, dried, using MgSO 4 , and concentrated.
  • Triethylamine (28 mg, 0.28 mmol) and anisoyl chloride (47 mg, 0.28 mmol) were added to a solution of 5-amino-2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-benzofuran (prepared as in Example 1(g) (150 mg, 0.23 mmol) in methylene chloride (5 ml) .
  • the thyroid hormone reporter cell lines are genetically engineered, mammalian cell lines expressing thyroid hormone receptor (ThR) ⁇ and ⁇ , respectively. These thyroid hormone responding cell lines contain stable integrated artificial transcription units comprised of a thyroid hormone response element (TRE) and core promoter sequences fused to a downstream reporter gene encoding a secreted form of alkaline phosphatase (ALP).
  • TRE thyroid hormone response element
  • ALP alkaline phosphatase
  • the cells express only very low levels of the ALP reporter protein.
  • the ThR is activated resulting in transcriptional activation of the ALP reporter gene, mediated through the TRE.
  • the expression of the ALP reporter protein in the TRAF ⁇ and TRAF ⁇ reporter cell lines, respectively, is induced by its natural agonist T3 in a concentration dependent manner.
  • the expression of the ALP reporter protein in the TRAF ⁇ and TRAF ⁇ reporter cell lines, respectively, is induced by its natural agonist T3 in a concentration dependent manner.
  • the level of thyroid hormone dependent ALP protein expressed can be determined indirectly by an enzymatic chemiluminescence assay as previously described (Advances in Steroid Analysis '93, editor: Gorog S., Proceedings of the 5th Symposium on the analysis of Steroids, Published by Akademiai Kiado, Budapest, Hungary, p. 57-67). Briefly, an aliquot of the conditioned cell culture medium is mixed with AMPPD (disodium 3-4-methoxyspiro(1,2-dioxetane-3,2'-tricyclo(3,3.1)decan)-4-yl) phenyl phosphate containing assay buffer and incubated at 37° C. for 20 minutes. AMPPD was purchased from Boule Diagnostic, Sweden.
  • the ALP in the medium sample dephosphorylates AMPPD generating an unstable intermediate which decomposes and emits light which is measured in a microplate format luminometer (Luminoskan, Labsystems, Finland).
  • the rate of light emission is directly proportional to the level of ALP present in the sample.
  • TRAF ⁇ and ⁇ cells show a stringent dependence on the presence of a thyroid hormone agonist for expression of the ALP reporter protein
  • the cells have to be stimulated by a low concentration of reference agonist (3,5,3'-triodothyronine (T3), Sigma) in order to analyse compounds for their antagonistic activity.
  • T3 reference agonist
  • the synthesized thyroid hormone derivatives were tested ( ⁇ T3 (reference agonist) for their capacity to influence, via interaction with the human thyroid hormone receptors ⁇ and ⁇ , respectively, the transcriptional activity of the ALP reporter gene i.e. their agonistic/antagonistic activity.
  • the TRAF ⁇ and ⁇ cells were seeded at a density of 2-2.5 ⁇ 10 4 cells/well in 96-well microtiterplates (suitable for growth of mammalian cells).
  • the cells were seeded in Coon's medium (without phenolred) (SVA, Uppsala, Sweden)+10% FCS (Gibco-BRL) (hormone stripped) and cultivated overnight at 37° C. and 5% CO 2 in a humidified incubator.
  • Hormone/test compounds added to the TRAF ⁇ and ⁇ reporter cells, respectively, per well in 96-well microtiter plates
  • concentration range from 10 -11 to 10 -6 M T3 as indicated on the x-axis, vehicle only (no T3 added) appears as 10 -12 M on the x-axis.
  • concentration range (example 1-3, 5): from 10 -9 to 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -10 M on the x-axis;
  • concentration range (example 4): from 10 -8 to 4 ⁇ 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -9 M on the x-axis;
  • concentration range (example 6): from 10 -7 to 4 ⁇ 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -8 M on the x-axis;
  • concentration range (example 7-10): from 5 ⁇ 10 -9 to 2 ⁇ 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -9 M on the x-axis;
  • concentration range (example 11-14): from 10 -7 to 3.2 ⁇ 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -8 M on the x-axis;
  • concentration range (example 15): from 10 -7 to 6.4 ⁇ 10 -5 M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 -8 M on the x-axis;
  • concentration range (example 1-3, 5): from 10 -9 to 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -10 M on the x-axis;
  • concentration range (example 4): from 10 -8 to 4 ⁇ 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -9 M on the x-axis;
  • concentration range (example 6): from 10 -7 to 4 ⁇ 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -8 M on the x-axis;
  • concentration range (example 7-10): from 5 ⁇ 10 -9 to 2 ⁇ 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -9 M on the x-axis;
  • concentration range (example 11-14): from 10 -7 to 3.2 ⁇ 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -8 M on the x-axis;
  • concentration range (example 15): from 10 -7 to 6.4 ⁇ 10 -5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and 1 nM T3 only (no test compound added) appears as 10 -8 M on the x-axis.
  • Examples 1-15 A series of dilutions of each compound produced (Examples 1-15) were allowed to compete with a fixed concentration (0.2 nM) of 125 I-T 3 for binding to the human thyroid hormone receptor ⁇ 1 (ThR ⁇ 1). In some examples, binding to the human thyroid hormone receptor ⁇ 1 (ThR ⁇ 1) was included.
  • IC 50 -value The concentration of compound required to inhibit 50% of the binding of radioactive labeled hormone was calculated from the curves. The resulting IC 50 -values expressed as logarithmic units are shown in table 1.
  • the range of affinities for the ThR ⁇ 1 is between 10 -5 .10 M. to 10 -5 .90 M.
  • Example 1 Three compounds (example 1,2 and 5) showed no antagonism to T3 in the ThR ⁇ reporter cell line but rather a concentration dependent augmention of the agonism of T3. Only example 5 displayed a similar activity in the ThR ⁇ reporter cell line.
  • One compound (example 11) showed partial agonist/antagonist activity in both ThR ⁇ and ⁇ reporter cell lines.
  • Two compounds (example 14 and 15) had a partial agonist/antagonist activity in the ThR ⁇ reporter cell line but no or only weak antagonist activity in the ThR ⁇ reporter cell line.

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JPH10504297A (ja) 1998-04-28
ATE172460T1 (de) 1998-11-15
EP0775129A1 (de) 1997-05-28
DE69505542D1 (de) 1998-11-26
AU694551B2 (en) 1998-07-23
WO1996005190A1 (en) 1996-02-22
ES2123287T3 (es) 1999-01-01
EP0775129B1 (de) 1998-10-21
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DE69505542T2 (de) 1999-06-02
CA2197185A1 (en) 1996-02-22

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